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Development of a cell-permeable adenine-derived probe for capture of nucleotide-binding proteins in living cells

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Chinese Chemical Letters 2024年第3期35卷 243-246页

作者： Lihong Liu Rui Chen Gang Xue Chenzhou Hao Weizhi Weng Zhengying Pan State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China

Adenine is an essential building block of genetic material and a range of coenzymes.Chemical probes containing an adenine moiety have been used in kinase profiling studies in cell lysates.Here we report that adenine-derived small-molecule probes with an activated ester reactive group can covalently modify a conserved lysine residue of protein kinases and capture a number of nucleotide-binding proteins within living cells.

关键词： Adenine-derived probe Cell-permeable Lysine residue protein kinases Nucleotide-binding proteins

Reprogramming plant specialized metabolism by manipulating protein kinases

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aBIOTECH 2021年第3期2卷 226-239页

作者： Ruiqing Lyu Sanjay K.Singh Yongliang Liu Barunava Patra Yan Zhou Bingwu Wang Sitakanta Pattanaik Ling Yuan Department of Plant and Soil Sciences and the Kentucky Tobacco Research and Development Center University of Kentucky1401 University DriveLexingtonKY 40546USA South China Botanical Garden Chinese Academy of SciencesGuangzhou 510650China Tobacco Breeding Center Yunnan Academy of Tobacco Agricultural SciencesKunming 650021YunnanChina

Being sessile,plants have evolved sophisticated mechanisms to balance between growth and defense to survive in the harsh environment.The transition from growth to defense is commonly achieved by factors,such as protein kinases(PKs)and transcription factors,that initiate signal transduction and regulate specialized metabolism.Plants produce an array of lineage-specific specialized metabolites for chemical defense and stress tolerance.Some of these molecules are also used by humans as drugs.However,many of these defense-responsive metabolites are toxic to plant cells and inhibitory to growth and development.Plants have,thus,evolved complex regulatory networks to balance the accumulation of the toxic metabolites.Perception of external stimuli is a vital part of the regulatory network.protein kinase-mediated signaling activates a series of defense responses by phosphorylating the target pro-teins and translating the stimulus into downstream cellular signaling.As biosynthesis of specialized metabolites is triggered when plants perceive stimuli,a possible connection between PKs and spe-cial ized meta bolism is well recognized.However,the roles of PKs in plant specialized metabolism have not received much attention until recently.Here,we summarize the recent advances in understanding PKs in plant specialized metabolism.We aim to highlight how the stimulatory signals are transduced,leading to the biosynthesis of corresponding metabolites.We discuss the post-translational regulation of specialized metabolism and provide insights into the mechanisms by which plants respond to the external signals.In addition,we propose possible strategies to increase the production of plant spe-cial ized metabolites in biotechnological applications using PKs.

关键词： Medicinal plants protein kinases MAP kinase Specialized metabolites Post-translational regulation Signal transd uction

Computational identification and analysis of neurodegenerative disease associated protein kinases in hominid genomes

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Genes & Diseases 2016年第3期3卷 228-237页

作者： Saranya Jayapalan Devika Subramanian Jeyakumar Natarajan Data Mining and Text Mining Lab Department of BioinformaticsBharathiar UniversityCoimbatoreIndia

protein kinases play an important role in the incidence of neurodegenerative diseases.However their incidence in non-human primates is found to be very low.Small differences among the genomes might influence the disease susceptibilities.The present study deals with finding the genetic differences of protein kinases in humans and their three closest evolutionary partners chimpanzee,gorilla and orangutan for three neurodegenerative diseases namely,Alzheimer’s,Parkinson’s and Huntington’s diseases.In total 47 human protein kinases associated with three neurodegenerative diseases and their orthologs from other three nonhuman primates were identified and analyzed for any possible susceptibility factors in humans.Multiple sequence alignment and pairwise sequence alignment revealed that,18 human protein kinases including DYRK1A,RPS6KB1,and GRK6 contained significant indels and substitutions.Further phosphorylation site analysis revealed that eight kinases including MARK2 and LTK contained sites of phosphorylation exclusive to human genomes which could be particular candidates in determining disease susceptibility between human and non-human primates.Final pathway analysis of these eight kinases and their targets revealed that these kinases could have long range consequences in important signaling pathways which are associated with neurodegenerative diseases.

关键词： Hominids Interaction analysis Neurodegenerative diseases Phosphorylation sites protein kinases

Salvianolic acid B promotes the invasion and migration of H_(2)O_(2)-induced HTR-8/Svneo trophoblast cells by upregulating matrix metalloproteinase-9 via the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B pathway

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Journal of Traditional Chinese Medicine 2023年第3期43卷 457-465页

作者： ZHAO Zhiqiang ZHANG Chong ZHU Yunxia Department of Gynecology and Obstetrics Beijing You'an Hospital of Capital Medical UniversityBeijing 100069China

OBJECTIVE:To elucidate the regulatory effects of salvianolic acid B(Sal B)on trophoblast cells in preeclampsia(PE).METHODS:3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide(MTT)assays were used to detect the viability of human extravillous trophoblast HTR-8/Svneo cells induced by H_(2)O_(2)following treatment with different concentrations of Sal B.The levels of oxidative stressrelated molecules,including superoxide dismutase,glutathione-Px and malondialdehyde were detected using corresponding kits.Cell apoptosis was detected using a Terminal deoxynucleotidyl transferase(Td T)d UTP NickEnd Labeling(TUNEL)assay,and the expression of apoptosis-related proteins was detected using western blot analysis.In the present study,wound healing and Transwell assays were performed to measure the levels of cell invasion and migration.Western blot analysis was also used to detect the expression levels of epithelialmesenchymal transition-related proteins.The mechanisms underlying Sal B were further investigated using reverse transcription-quantitative real-time polymerase chain reaction(RT-q PCR)and western blot analysis,to determine the expression levels of matrix metallopeptidase 9(MMP-9)and phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)/protein kinase B(Akt).RESULTS:Sal B increased the activity of HTR-8/Svneo cells,inhibited oxidative damage and promoted the invasion and migration of trophoblast cells induced by H_(2)O_(2).Furthermore,the expression levels of MMP-9 and members of the PI3K/Akt signaling pathway were significantly decreased.The pathway agonist,LY294002,and MMP-9 inhibitor,GM6001,reversed the effects of Sal B on H_(2)O_(2)-induced cells.CONCLUSIONS:Sal B promoted the invasion and migration of H_(2)O_(2)-induced HTR-8/Svneo trophoblast cells by upregulating MMP-9 via the PI3K/Akt signaling pathway.

关键词： sennosides matrix metallopeptidase 9 phosphatidylinositol 3-kinase protein kinases HTR-8/Svneo trophoblast cell invasion migration

Urocortin and cardiovascular protection

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Acta Pharmacologica Sinica 2004年第3期25卷 3-11页

作者： Chi-wai LAU Yau-chi CHAN Suk-ying TSANG Franky Leung CHAN China Department of Anatomy The Chinese University of Hong Kong

Urocortin and other hypothalamus corticotropin-releasing factor (CRF) polypeptides play biologically diverse roles in the stress, cardiovascular and inflammatory responses by acting on central and peripheral CRF receptors. Urocortin shows a significantly high sequence homology to CRF, and the concurrent expression of type-2 CRF (CRF2) receptors with urocortin in the heart suggests that urocortin may play a physiological role in the cardiac function. Urocortin is thought to be the endogenous agonist producing the cardiovascular actions previously attributed to CRF. This review highlights the current novel findings on the molecular and cellular mechanisms by which urocortin may exert its cardiovascular protective action.

关键词： urocortin corticotropin-releasing hormone vascular smooth muscle heart vasodilaion second messenger system protein kinases

Major regulatory mechanisms involved in sperm motility

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Asian Journal of Andrology 2017年第1期19卷 5-14页

作者： Rute Pereira Rosalia Sa Alberto Barros Mario Sousa Department of Microscopy Laboratory of Cell Biology Institute of Biomedical Sciences Abel Salazar University of Porto (ICBAS-UP) Rua Jorge Viterbo Ferreira 2284050-313 Porto Portugal and Multidisciplinary Unit for Biomedical Research-UMIB ICBAS-UP Centre for Reproductive Genetics Alberto Barros Av. do Bessa 2401° Dto. Frente 4100-012 Porto Portugal Department of Genetics Faculty of Medicine University of Porto. Alameda Prof. Hernani Monteiro 4200-319 Porto Portugal and Institute of Health Research an Innovation (13S) University of Porto Portugal.

The genetic bases and molecular mechanisms involved in the assembly and function of the flagellum components as well as in the regulation of the flagellar movement are not fully understood, especially in humans. There are several causes for sperm immotility, of which some can be avoided and corrected, whereas other are related to genetic defects and deserve full investigation to give a diagnosis to patients. This review was performed after an extensive literature search on the online databases PubMed, ScienceDirect, and Web of Science. Here, we review the involvement of regulatory pathways responsible for sperm motility, indicating possible causes for sperm immotility. These included the calcium pathway, the cAMP-dependent protein kinase pathway, the importance of kinases and phosphatases, the function of reactive oxygen species, and how the regulation of cell volume and osmolarity are also fundamental components. We then discuss main gene defects associated with specific morphological abnormalities. Finally, we slightly discuss some preventive and treatments approaches to avoid development of conditions that are associated with unspecified sperm immotility. We believe that in the near future, with the development of more powerful techniques, the genetic causes of sperm immotility and the regulatory mechanisms of sperm motility will be better understand, thus enabling to perform a full diagnosis and uncover new therapies.

关键词： antioxidants calcium membrane channels protein kinases sperm genetic abnormalities sperm motility

Targeting RAS phosphorylation in cancer therapy:Mechanisms and modulators

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3433-3446页

作者： Yuran Qiu Yuanhao Wang Zongtao Chai Duan Ni Xinyi Li Jun Pu Jie Chen Jian Zhang Shaoyong Lu Chuan Lv Mingfei Ji Department of Urology Changzheng HospitalNaval Military Medical UniversityShanghai 200003China Department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China Department of Hepatic Surgery VI Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China Department of Cardiology Renji HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200120China Department of Plastic Surgery Changhai HospitalNaval Military Medical UniversityShanghai 200438China

RAS,a member of the small GTPase family,functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state.RAS gain-of-function mutations are one of the leading causes in human oncogenesis,accounting for w19%of the global cancer burden.As a well-recognized target in malignancy,RAS has been intensively studied in the past decades.Despite the sustained efforts,many failures occurred in the earlier exploration and resulted in an‘undruggable’feature of RAS proteins.Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins.Therefore,the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties.A better understanding of RAS phosphorylation can contribute to future therapeutic strategies.In this review,we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways.Importantly,the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.

关键词： RAS Phosphorylation Undruggable protein kinases Allostery

Neuroprotection of quercetin on central neurons against chronic high glucose through enhancement of Nrf2/Glo-1 mediated by phosphorylation regulation

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中国药理学与毒理学杂志 2017年第10期31卷 995-996页

作者： Meng-ya ZHANG Xiao-li LIU Yao-wu LIU Xuzhou Medical University Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical University Department of PharmacologySchool of Pharmacy

OBJECTIVE To investigate the neuroprotective effects of quercetin on central neurons against chronic high glucose in central neurons,in relation to Nrf2/ARE/Glo-1 activation.METHODS SH-SY5Y cells were cultured with high glucose(HG,70 mmol·L^(-1)),4-fold of the normal glucose(17.5 mmol·L^(-1)).Quercetin was set three concentrations(5,10,20μmol·L^(-1)),with Nrf2 activator sulforaphane(SFN)as a positive group(2.5μmol·L^(-1)).After 72 h,cells were collected for glyoxalase 1(Glo-1)activity and GSH level were by spectrophotometry;advanced glycation end-products(AGEs)as well as nuclear Nrf2 and p-Nrf2 levels by immunofluorescence;Glo-1,γ-glutamycysteine synthase(γ-GCS),Nrf2 and p-Nrf2 protein levels by Western blotting,and Glo-1 andγ-GCS m RNA levels by real-time qP CR.RESULTS Quercetin increased the cell viability of SH-SY5Y cells,and upregulated the levels of Glo-1 activity,protein,and m RNA in SH-SY5Y cells cultured with HG,accompanied by the elevated levels of glutathione,a cofactor of Glo-1 activity,and the reduced levels of AGEs.Meanwhile,quercetin could increase p-Nrf2 and Nrf2 levels in nucleus as well as p-Nrf2 levels in cytosol of SH-SY5Y cells exposed to chronic HG,accompanied by the elevated protein expression and m RNA levels ofγ-GCS,a known target gene of Nrf2/ARE signaling.Moreover,a PKC activator or a p38MAPK inhibitor pretreatment could significantly increase the protein expression ofγ-GCS in HG condition,but an alkylating agent for sulfydryl of cysteine in Keap 1,a negative regulator of Nrf2,pretreatment only showed an increased tendency ofγ-GCS protein,compared with without pretreatment;however,after pretreatment with those tool drugs,co-treatment with quercetin and HG had similar results to those of single tool drug pretreatment followed by HG exposure.CONCLUSION Firstly,quercetin can enhance Glo-1 function in central neurons,which is mediated by activation of Nrf2/ARE pathway,then exerts the neuroprotection against HG induced damage;moreover,PKC and p38 MAPK pathways may be involved in Nrf2 inactiva

关键词： glyoxalase 1 quercetin nuclear factor erythroid-2-related factor 2 high glucose central neurons protein kinases

Identification of Secondary Structure of Extracellular Signal Regulated Kinase (ERK) Interacting proteins and Their Domain: An in Silico Study

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World Journal of Neuroscience 2021年第1期11卷 67-89页

作者： Kurrey Khuleshwari Paramanik Vijay Cellular and Molecular Neurobiology & Drug Targeting Laboratory Department of Zoology Indira Gandhi National Tribal University Amarkantak (MP) (MP)-484 887 India

ERK is involved in multiple cell signaling pathways through its interacting proteins. By in silico analysis, earlier we have identified 22 putative ERK interacting proteins namely;ephrin type-B receptor 2 isoform 2 precursor (EPHB2), mitogen-activated protein kinase 1 (MAPK1), interleukin-17 receptor D precursor (IL17RD), WD repeat domain containing 83 (WDR83), tescalcin (Tesc), mitogen-activated protein kinase kinase kinase 4 (MAPP3K4), kinase suppressor of Ras2 (KSR2), mitogen-activated protein kinase kinase 6 (MAP3K6), UL16 binding protein 2 (ULBP2), UL16 binding protein 1 (ULBP1), dual specificity phosphatase 14 (DUSP14), dual specificity phosphatase 6 (DUSP6), hyaluronan-mediated motility receptor (RHAMM), kinase D interacting substrate of 220 kDa (KININS220), membrane-associated guanylate kinase (MAGI3), phosphoprotein enriched in astrocytes 15 (PEA15), typtophenyl-tRNA synthetase, cytoplasmic (WARS), dual specificity phosphatase 9 (DUSP9), mitogen-activated protein kinase kinase kinase 1 (MAP3K1), UL16 binding protein 3 (ULBP3), SLAM family member 7 isoform a precursor (SLAMMF7) and mitogen activated protein kinase kinase kinase 11 (MAP3K11) ( ERK Secondary Structure Motif Scan Random Coils Alpha Helix protein kinases